Immune Turn-Down

Oxygen-sensing proteins may facilitate tumor metastasis to the lungs

An immune mechanism that permits the lungs to tolerate exposure to harmless antigens also helps metastatic cancer cells colonize the organ.

Nearly 90 percent of cancer deaths are caused by tumors metastasizing to distant organs. The lungs are a common site of metastasis for primary bladder, breast, colon, kidney, ovary, pancreas, bone, rectal, stomach, thyroid and uterine cancers, as well as melanoma.

The researchers found that the highly oxygenated lung microenvironment enables cancer cells to spread to the lung more easily.

“Every time we inhale, we bring things into our lungs that could produce a pretty dramatic and potentially harmful immune response—but they usually don’t because in a normal, healthy state our immune systems are set up to accommodate for this,” explains David Clever, PhD, first author of the manuscript and a current medical student at Ohio State. Clever completed this research under the mentorship of Nicholas Restifo, MD, of the National Cancer Institute (NCI) during the doctoral portion of his Medical Scientist Training Program.

Specifically, the team discovered that certain oxygen-sensing prolyl-hydroxylase (PHD) proteins limit inflammatory responses by T cells in the lung microenvironment. At the same time, those proteins also limit immune responses against cancer cells, facilitating metastasis.

Blocking the PHD proteins pharmacologically or by using mice that lack the proteins in T cells enhanced T-cell responses against cancer and limited metastasis to the lungs.

The results contribute a new immunological basis for the predisposition of many cancers to metastasize to the lungs that could help scientists develop new therapies to prevent this.

“Although our finding is in mice,” Restifo says, “we are eager to test whether disrupting the oxygen-sensing machinery in T cells with drugs, genetics, or regulation of environmental oxygen—will enhance the efficacy of T-cell-mediated immune therapies for cancer in humans.”